Phenylketonuria (PKU) is caused by the deficiency of the hepatic enzyme Phenylalanine Hydroxylase, which catalyses the conversion of the aminoacid Phenylalanine (Phe) into Tyrosine. Clinical manifestations of the disease are due to the accumulation of Phe in the brain. Indeed, untreated PKU is associated with intellectual disability, autism, seizures, and motor deficits. Early-treatment of PKU is aimed at decreasing the blood Phe concentration, which is considered to be correlated with brain Phe concentrations. Despite the favorable clinical outcome of early treated PKU patients, a lower than expected intelligence quotient (IQ) and neuropsychological and psychiatric problems, neuroimaging alterations remain challenging aspects of the disease and the possible targets for future improvement of the treatment. On the other hand, due to the difficulty to adhere to the diet in adulthood, many patients discontinue or relax the diet and nevertheless show a completely normal cognitive functioning. This remarkable variability in the outcome suggests the existence of an individual vulnerability to Phe, which cannot be deduced from the biochemical phenotype of the disease. Discovering possible biomarker of such susceptibility or resilience may help in personalizing the therapy and improve the outcome of the disease. The aim of present project is to explore the variation of brain connectivity in adult PKU patients under different values of blood and brain Phe. Two following neuropsychological, morphological (brain MRI), functional (resting state fMRI), and biochemical (brain 1H-MRS) will be performed in 10 subjects affected by classical PKU (diagnostic blood Phe level > 1200 µmol/l) at interval of 4 weeks. The two examinations will be planned in order to collect individual data under a low ( 500 µmol/l) levels of blood Phe, respectively. We expect to characterize individual variation denoting age-related and/or subject-related vulnerability to Phe.
While the intellectual outcome is the result of a complex constellation of genetic and epigenetic events in normal as well in pathological conditions, American and European guidelines (Vockley et al, 2014; vanSpronsen et al, 2017) adopted blood Phe, which is a surrogate of brain Phe, as the only variable predicting neurological outcome in early treated PKU subjects. As consequence, the blood Phe levels is the only factors affecting the treatment options. Despite it is well known that almost 10% of untreated PKU patient may have a normal clinical outcome (Ramus et al. Pediatric Research, 1999, 45), factors affecting this resilience to the disease are not known and could not be included in decision trees suggested by the two guide lines. However, the awareness of he extreme variability in the outcome of early treated subjects, which suggests the occurrence of other environmental and biological factors affecting the prognosis of the disease, is expressed in both the guide lines. Finally, age-specific vulnerability of PKU patients has been recently demonstrated by neurophysiological and neuropsychological studies (Leuzzi et al, Front Pediatr 2014, 2; Manti et al, JIMD 2017,40).
The target of present project is the study of the individual susceptibility or resilience to the amino acid Phe, the main causal factor involved in the pathogenesis of neurological impairment in patients with PKU. The explicit aim of our study is to detect individual phenotypic characteristics which may be part of a decision algorithm for the therapy (that will include biochemical as well individual biomarkers of vulnerability to Phe). Present research project has been addressed by the recent interest in precision medicine, more specifically in personalized medicine, which take into account the biological individuality of the patients as criterion for treatment tailoring. The psychological burden of PKU patients and the economical cost of incoming new treatment for PKU require such a new approach to the treatment.